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Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 23639

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Prof. Dr. Alexander Tonevitsky

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1. Faculty of Biology and Biotechnology, National Research University Higher School of Economics, 101000 Moscow, Russia
2. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia
3. Far Eastern Federal University, 690091 Vladivostok, Russia
Interests: mechanisms of intracellular transport of proteins and the creation of models for selective cytotoxic effects on target cells; molecular mechanisms of cancer progression; the role of gene expression regulation by miRNAs for homeostasis and in pathology processes; microphysiological systems - Organ-on-a-Chip; development of methods for non-invasive study of key mechanisms of homeostasis

Dr. Diana Maltseva

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Dear Colleagues,

Toxic proteins naturally occur in a wide variety of species, where they play a major role in defense against feeding animals and various insects and pathogens, giving them an advantage in a particular niche shaped by evolution. Protein toxins are present in human foods and cosmetics and play a major role as etiological agents in the development of diseases. Many bacterial and plant toxins utilize cellular mechanisms of retrograde vesicular transport to be delivered into the cell, particularly into the cytoplasm, where they realize their cytotoxic potential. Some toxins serve as powerful tools for studying endocytic and protein degradation machineries. Because of their cytotoxicity, protein toxins show great potential in broad therapeutic and biotechnological applications, including vaccinations, treatment of chronic migraines and autoimmunity diseases, and anticancer therapy. This Special Issue will focus on the novel insights concerning the mechanisms by which natural and bioengineered protein toxins enter into cell, their achievements in target cell delivery, their utilization of different cellular mechanisms for the development of a toxic effect, as well as on new strategies and recent strides taken with respect to the application of protein toxins. Fundamental, functional, and methodological studies are welcome, as well as clinical studies with biomolecular experiments and reviews highlighting the most significant protein toxin-related breakthroughs of the last decade.

Prof. Dr. Alexander Tonevitsky
Dr. Diana Maltseva
Guest Editors

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Keywords

protein toxin
immunotoxin
intracellular vesicle transport
toxin fusions
biotechnology
endocytosis
retrograde transport
transcytosis
protein degradation
ERAD
proteasome degradation
endoplasmic reticulum
ER
translocation
anticancer therapy
clinical applications
therapeutic applications

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Published Papers (7 papers)

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Research

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17 pages, 2198 KiB

Open AccessArticle

Helicobacter pylori Urease: Potential Contributions to Alzheimer’s Disease

by Augusto F. Uberti, Natalia Callai-Silva, Matheus V. C. Grahl, Angela R. Piovesan, Eduarda G. Nachtigall, Cristiane R. G. Furini and Celia Regina Carlini

Int. J. Mol. Sci. 2022, 23(6), 3091; https://doi.org/10.3390/ijms23063091 - 13 Mar 2022

Cited by 21 | Viewed by 3970

Abstract

Alzheimer’s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori’s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood–brain barrier and directly induce tau’s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50–300 nM) produced reactive oxygen species (ROS) and had an increased [Ca²⁺]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, and showed reduced viability. Rats received daily i.p., HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3β levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications)

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15 pages, 2747 KiB

Open AccessArticle

Latrotoxin-Induced Neuromuscular Junction Degeneration Reveals Urocortin 2 as a Critical Contributor to Motor Axon Terminal Regeneration

by Giorgia D’Este, Marco Stazi, Samuele Negro, Aram Megighian, Florigio Lista, Ornella Rossetto, Cesare Montecucco, Michela Rigoni and Marco Pirazzini

Int. J. Mol. Sci. 2022, 23(3), 1186; https://doi.org/10.3390/ijms23031186 - 21 Jan 2022

Cited by 1 | Viewed by 2820

Abstract

We used α-Latrotoxin (α-LTx), the main neurotoxic component of the black widow spider venom, which causes degeneration of the neuromuscular junction (NMJ) followed by a rapid and complete regeneration, as a molecular tool to identify by RNA transcriptomics factors contributing to the structural and functional recovery of the NMJ. We found that Urocortin 2 (UCN2), a neuropeptide involved in the stress response, is rapidly expressed at the NMJ after acute damage and that inhibition of CRHR2, the specific receptor of UCN2, delays neuromuscular transmission rescue. Experiments in neuronal cultures show that CRHR2 localises at the axonal tips of growing spinal motor neurons and that its expression inversely correlates with synaptic maturation. Moreover, exogenous UCN2 enhances the growth of axonal sprouts in cultured neurons in a CRHR2-dependent manner, pointing to a role of the UCN2-CRHR2 axis in the regulation of axonal growth and synaptogenesis. Consistently, exogenous administration of UCN2 strongly accelerates the regrowth of motor axon terminals degenerated by α-LTx, thereby contributing to the functional recovery of neuromuscular transmission after damage. Taken together, our results posit a novel role for UCN2 and CRHR2 as a signalling axis involved in NMJ regeneration. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications)

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18 pages, 2424 KiB

Open AccessArticle

Selective Enhancement of the Cell-Permeabilizing Activity of Adenylate Cyclase Toxin Does Not Increase Virulence of Bordetella pertussis

by Jana Holubova, Attila Juhasz, Jiri Masin, Ondrej Stanek, David Jurnecka, Adriana Osickova, Peter Sebo and Radim Osicka

Int. J. Mol. Sci. 2021, 22(21), 11655; https://doi.org/10.3390/ijms222111655 - 28 Oct 2021

Cited by 3 | Viewed by 2375

Abstract

The whooping cough agent, Bordetella pertussis, secretes an adenylate cyclase toxin–hemolysin (CyaA, ACT, or AC-Hly) that catalyzes the conversion of intracellular ATP to cAMP and through its signaling annihilates the bactericidal activities of host sentinel phagocytes. In parallel, CyaA permeabilizes host cells by the formation of cation-selective membrane pores that account for the hemolytic activity of CyaA. The pore-forming activity contributes to the overall cytotoxic effect of CyaA in vitro, and it has previously been proposed to synergize with the cAMP-elevating activity in conferring full virulence on B. pertussis in the mouse model of pneumonic infection. CyaA primarily targets myeloid phagocytes through binding of their complement receptor 3 (CR3, integrin α_Mβ₂, or CD11b/CD18). However, with a reduced efficacy, the toxin can promiscuously penetrate and permeabilize the cell membrane of a variety of non-myeloid cells that lack CR3 on the cell surface, including airway epithelial cells or erythrocytes, and detectably intoxicates them by cAMP. Here, we used CyaA variants with strongly and selectively enhanced or reduced pore-forming activity that, at the same time, exhibited a full capacity to elevate cAMP concentrations in both CR3-expressing and CR3-non-expressing target cells. Using B. pertussis mutants secreting such CyaA variants, we show that a selective enhancement of the cell-permeabilizing activity of CyaA does not increase the overall virulence and lethality of pneumonic B. pertussis infection of mice any further. In turn, a reduction of the cell-permeabilizing activity of CyaA did not reduce B. pertussis virulence any importantly. These results suggest that the phagocyte-paralyzing cAMP-elevating capacity of CyaA prevails over the cell-permeabilizing activity of CyaA that appears to play an auxiliary role in the biological activity of the CyaA toxin in the course of B. pertussis infections in vivo. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications)

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17 pages, 2414 KiB

Open AccessArticle

Proteus mirabilis Urease: Unsuspected Non-Enzymatic Properties Relevant to Pathogenicity

by Matheus V. C. Grahl, Augusto F. Uberti, Valquiria Broll, Paula Bacaicoa-Caruso, Evelin F. Meirelles and Celia R. Carlini

Int. J. Mol. Sci. 2021, 22(13), 7205; https://doi.org/10.3390/ijms22137205 - 4 Jul 2021

Cited by 14 | Viewed by 3816

Abstract

Infection by Proteus mirabilis causes urinary stones and catheter incrustation due to ammonia formed by urease (PMU), one of its virulence factors. Non-enzymatic properties, such as pro-inflammatory and neurotoxic activities, were previously reported for distinct ureases, including that of the gastric pathogen Helicobacter pylori. Here, PMU was assayed on isolated cells to evaluate its non-enzymatic properties. Purified PMU (nanomolar range) was tested in human (platelets, HEK293 and SH-SY5Y) cells, and in murine microglia (BV-2). PMU promoted platelet aggregation. It did not affect cellular viability and no ammonia was detected in the cultures’ supernatants. PMU-treated HEK293 cells acquired a pro-inflammatory phenotype, producing reactive oxygen species (ROS) and cytokines IL-1β and TNF-α. SH-SY5Y cells stimulated with PMU showed high levels of intracellular Ca²⁺ and ROS production, but unlike BV-2 cells, SH-SY5Y did not synthesize TNF-α and IL-1β. Texas Red-labeled PMU was found in the cytoplasm and in the nucleus of all cell types. Bioinformatic analysis revealed two bipartite nuclear localization sequences in PMU. We have shown that PMU, besides urinary stone formation, can potentially contribute in other ways to pathogenesis. Our data suggest that PMU triggers pro-inflammatory effects and may affect cells beyond the renal system, indicating a possible role in extra-urinary diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications)

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14 pages, 1195 KiB

Open AccessArticle

A cis-Acting Mutation in the PxABCG1 Promoter Is Associated with Cry1Ac Resistance in Plutella xylostella (L.)

by Jianying Qin, Fan Ye, Linzheng Xu, Xuguo Zhou, Neil Crickmore, Xiaomao Zhou, Youjun Zhang and Zhaojiang Guo

Int. J. Mol. Sci. 2021, 22(11), 6106; https://doi.org/10.3390/ijms22116106 - 5 Jun 2021

Cited by 16 | Viewed by 3097

Abstract

The molecular mechanisms of insect resistance to Cry toxins generated from the bacterium Bacillus thuringiensis (Bt) urgently need to be elucidated to enable the improvement and sustainability of Bt-based products. Although downregulation of the expression of midgut receptor genes is a pivotal mechanism of insect resistance to Bt Cry toxins, the underlying transcriptional regulation of these genes remains elusive. Herein, we unraveled the regulatory mechanism of the downregulation of the ABC transporter gene PxABCG1 (also called Pxwhite), a functional midgut receptor of the Bt Cry1Ac toxin in Plutella xylostella. The PxABCG1 promoters of Cry1Ac-susceptible and Cry1Ac-resistant strains were cloned and analyzed, and they showed clear differences in activity. Subsequently, a dual-luciferase reporter assay, a yeast one-hybrid (Y1H) assay, and RNA interference (RNAi) experiments demonstrated that a cis-mutation in a binding site of the Hox transcription factor Antennapedia (Antp) decreased the promoter activity of the resistant strain and eliminated the binding and regulation of Antp, thereby enhancing the resistance of P. xylostella to the Cry1Ac toxin. These results advance our knowledge of the roles of cis- and trans-regulatory variations in the regulation of midgut Cry receptor genes and the evolution of Bt resistance, contributing to a more complete understanding of the Bt resistance mechanism. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications)

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17 pages, 2019 KiB

Open AccessArticle

The Role of Cholesterol on Triterpenoid Saponin-Induced Endolysosomal Escape of a Saporin-Based Immunotoxin

by Wendy S. Smith, David A. Johnston, Harrison J. Wensley, Suzanne E. Holmes, Sopsamorn U. Flavell and David J. Flavell

Int. J. Mol. Sci. 2020, 21(22), 8734; https://doi.org/10.3390/ijms21228734 - 19 Nov 2020

Cited by 8 | Viewed by 2419

Abstract

Cholesterol seems to play a central role in the augmentation of saporin-based immunotoxin (IT) cytotoxicity by triterpenoid saponins. Endolysosomal escape has been proposed as one mechanism for the saponin-mediated enhancement of targeted toxins. We investigated the effects of lipid depletion followed by repletion on Saponinum album (SA)-induced endolysosomal escape of Alexa Fluor labelled saporin and the saporin-based immunotoxin OKT10-SAP, directed against CD38, in Daudi lymphoma cells. Lipid deprived cells showed reduced SA-induced endolysosomal escape at two concentrations of SA, as determined by a flow cytometric method. The repletion of membrane cholesterol by low density lipoprotein (LDL) restored SA-induced endolysosomal escape at a concentration of 5 µg/mL SA but not at 1 µg/mL SA. When LDL was used to restore the cholesterol levels in lipid deprived cells, the SA augmentation of OKT10-SAP cytotoxicity was partially restored at 1 µg/mL SA and fully restored at 5 µg/mL SA. These results suggest that different mechanisms of action might be involved for the two different concentrations of SA and that endosomal escape may not be the main mechanism for the augmentation of saporin IT cytotoxicity by SA at the sub-lytic concentration of 1 µg/mL SA. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications)

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Review

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24 pages, 1661 KiB

Open AccessReview

Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology

by Olga Shilova, Elena Shramova, Galina Proshkina and Sergey Deyev

Int. J. Mol. Sci. 2021, 22(9), 4975; https://doi.org/10.3390/ijms22094975 - 7 May 2021

Cited by 18 | Viewed by 4105

Abstract

Cancer cells frequently overexpress specific surface receptors providing tumor growth and survival which can be used for precise therapy. Targeting cancer cell receptors with protein toxins is an attractive approach widely used in contemporary experimental oncology and preclinical studies. Methods of targeted delivery of toxins to cancer cells, different drug carriers based on nanosized materials (liposomes, nanoparticles, polymers), the most promising designed light-activated toxins, as well as mechanisms of the cytotoxic action of the main natural toxins used in modern experimental oncology, are discussed in this review. The prospects of the combined therapy of tumors based on multimodal nanostructures are also discussed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications)

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